Germinal center reentries of BCL2-overexpressing B cells drive follicular lymphoma progression

It has recently been demonstrated that memory B cells can reenter and reengage germinal center (GC) reactions, opening the possibility that multi-hit lymphomagenesis gradually occurs throughout life during successive immunological challenges. Here, we investigated this scenario in follicular lymphom...

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Bibliographic Details
Published in:The Journal of clinical investigation 2014-12, Vol.124 (12), p.5337-5351
Main Authors: Sungalee, Stéphanie, Mamessier, Emilie, Morgado, Ester, Grégoire, Emilie, Brohawn, Philip Z, Morehouse, Christopher A, Jouve, Nathalie, Monvoisin, Céline, Menard, Cédric, Debroas, Guilhaume, Faroudi, Mustapha, Mechin, Violaine, Navarro, Jean-Marc, Drevet, Charlotte, Eberle, Franziska C, Chasson, Lionel, Baudimont, Fannie, Mancini, Stéphane J, Tellier, Julie, Picquenot, Jean-Michel, Kelly, Rachel, Vineis, Paolo, Ruminy, Philippe, Chetaille, Bruno, Jaffe, Elaine S, Schiff, Claudine, Hardwigsen, Jean, Tice, David A, Higgs, Brandon W, Tarte, Karin, Nadel, Bertrand, Roulland, Sandrine
Format: Article
Language:English
Subjects:
Animals
Antigens
B cells
B-Lymphocyte Subsets - metabolism
B-Lymphocyte Subsets - pathology
Biomedical research
Cell Movement
Cloning
Cytidine Deaminase - genetics
Cytidine Deaminase - metabolism
Development and progression
Female
Gene expression
Gene Expression Regulation, Neoplastic
Genetic aspects
Genomes
Humans
Immune system
Life Sciences
Lymphoma
Lymphoma, Follicular - genetics
Lymphoma, Follicular - metabolism
Lymphoma, Follicular - pathology
Lymphomas
Male
Mice
Mice, Transgenic
Neoplasms, Experimental - genetics
Neoplasms, Experimental - metabolism
Neoplasms, Experimental - pathology
Physiological aspects
Proto-Oncogene Proteins c-bcl-2 - biosynthesis
Proto-Oncogene Proteins c-bcl-2 - genetics
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Summary:It has recently been demonstrated that memory B cells can reenter and reengage germinal center (GC) reactions, opening the possibility that multi-hit lymphomagenesis gradually occurs throughout life during successive immunological challenges. Here, we investigated this scenario in follicular lymphoma (FL), an indolent GC-derived malignancy. We developed a mouse model that recapitulates the FL hallmark t(14;18) translocation, which results in constitutive activation of antiapoptotic protein B cell lymphoma 2 (BCL2) in a subset of B cells, and applied a combination of molecular and immunofluorescence approaches to track normal and t(14;18)(+) memory B cells in human and BCL2-overexpressing B cells in murine lymphoid tissues. BCL2-overexpressing B cells required multiple GC transits before acquiring FL-associated developmental arrest and presenting as GC B cells with constitutive activation-induced cytidine deaminase (AID) mutator activity. Moreover, multiple reentries into the GC were necessary for the progression to advanced precursor stages of FL. Together, our results demonstrate that protracted subversion of immune dynamics contributes to early dissemination and progression of t(14;18)(+) precursors and shapes the systemic presentation of FL patients.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI72415